Psoriasis is a chronic skin disease characterized by inflamed, scaly and frequently disfiguring skin lesions. The skin lesions show hyperproliferation and altered terminal differentiation leading to parakeratosis and desquamation. Caspase-14 is a nonapoptotic caspase family member and is involved in terminal differentiation and is essential for accelerated cornification in response to barrier disruption and for the formation of normal corneocytes. Emerging data and our compelling preliminary studies suggest that caspase-14 expression is substantially down-regulated in human psoriatic lesions compared to corresponding samples from nonlesional skin of the same individuals and from normal control individual. Thus, identifying naturally occurring anti-inflammatory agents which possess the ability to induce terminal differentiation and inhibit hyperproliferation could be useful for the treatment of psoriasis. Delphinidin, a major anthocyanidin abundantly present in pigmented fruits and vegetables, possesses anti-inflammatory and anti-proliferative activities. Our preliminary unpublished studies are noteworthy where we have demonstrated that delphinidin treatment induced the protein and mRNA expression of procaspase-14 in normal human epidermal keratinocytes (NHEK). Delphinidin also induced the processing of caspase-14 into catalytically active subunits p10 and p20. We also found a significant increase in the protein and mRNA expression of involucrin and transglutaminase-1 in delphinidin treated NHEK. Furthermore, delphinidin treatment to NHEK increased the protein expression of AP-1 subunits and NF-:B subunits p50 and RelB. Importantly, delphinidin under identical treatment conditions did not result in induction of apoptosis. This remarkable distinction forms the basis of this proposal which is designed to investigate the effect of delphinidin on keratinocyte differentiation and hyperproliferation both in in vitro human reconstituted skin model and in preclinical in vivo settings. The hypothesis to be tested in this proposal is that "delphinidin will induce differentiation and accelerate cornification that will in turn reduce the severity of psoriasiform lesions by inducing the expression of caspase-14 and suppression of cell proliferation without inducing apoptosis". To test our hypothesis, the following specific aims are proposed: (i) To investigate whether delphinidin treatment accelerates the process of cornification through increased expression and processing of caspase-14 in three-dimensional human reconstituted skin model, (ii) To investigate whether the effect of delphinidin on caspase-14 expression, cellular localization, and processing is mediated through AP-1 and NF-:B pathways in three-dimensional human reconstituted skin model, and (iii) To establish whether caspase-14 is associated with reduced symptoms of epidermal pathology with delphinidin treatment under in vivo situation by employing flaky skin (fsn/fsn) mice and flaky skin (fsn/fsn) caspase 14-/- mice. This proposal will establish the role of caspase-14 for treatment of psoriasis and in addition will draw attention to the use of delphinidin an anthocyanidin for its treatment. PUBLIC HEALTH RELEVANCE: This proposal may be extremely valuable pre-clinical approach for the development of new strategies and to define a novel agent delphinidin present in pigmented fruits and vegetables for the treatment of psoriasis and could also be useful in other hyperproliferative skin disorders.